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Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV

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What Not to Use

Last Updated: October 17, 2017; Last Reviewed: October 17, 2017

Some antiretroviral (ARV) regimens or components are not generally recommended because of suboptimal antiviral potency, unacceptable toxicities, or pharmacologic concerns. These are summarized below.

Antiretroviral Drugs Not Recommended

The following ARV drugs are no longer recommended for use because of suboptimal antiviral potency, unacceptable toxicities, high pill burden, or pharmacologic concerns: delavirdine (DLV), didanosine (ddI), indinavir (IDV), nelfinavir (NFV), and stavudine (d4T).

Antiretroviral Regimens Not Recommended

Nucleoside reverse transcriptase inhibitor (NRTI) monotherapy is inferior to dual-NRTI therapy.1 Protease inhibitor (PI) monotherapy is inferior to combination antiretroviral therapy (ART).2-6 Integrase strand transfer inhibitor (INSTI) monotherapy has resulted in virologic rebound and INSTI resistance (AI).7,8

Dual-NRTI Regimens
These regimens are inferior to triple-drug combination regimens (AI).9

Triple-NRTI Regimens
Triple-NRTI regimens have suboptimal virologic activity10-12 or a lack of data (AI).

Antiretroviral Components Not Recommended

Atazanavir plus Indinavir
Both PIs can cause Grade 3 to 4 hyperbilirubinemia and jaundice. Additive adverse effects may be possible when these agents are used concomitantly (AIII).

Cobicistat plus Ritonavir as Pharmacokinetic Enhancers
This combination may be prescribed inadvertently, which may result in additive CYP3A4 enzyme inhibition and may further increase the concentrations of ARV drugs or other concomitant medications (see Tables 19a and 19d).

Didanosine plus Stavudine
The combination of ddI and d4T can result in peripheral neuropathy, pancreatitis, and lactic acidosis, and it has been implicated in the deaths of several pregnant women (AII).13

Didanosine plus Tenofovir Disoproxil Fumarate
Tenofovir disoproxil fumarate (TDF) increases ddI concentrations,14 serious ddI-associated toxicities,15,16 immunologic nonresponse,17 early virologic failure,18,19 and resistance18,20 (AII).

Two Non-Nucleoside Reverse Transcriptase Inhibitor Combinations
Excess clinical adverse events and treatment discontinuation were reported in patients randomized to receive treatment with two non-nucleoside reverse transcriptase inhibitors (NNRTIs).21 Efavirenz (EFV) and nevirapine (NVP) are enzyme inducers, and both of these drugs can reduce concentrations of etravirine (ETR) and rilpivirine (RPV) (AI).22

Emtricitabine plus Lamivudine
Both drugs have similar resistance profiles and have minimal additive antiviral activity. Inhibition of intracellular phosphorylation may occur in vivo (AIII).23

Etravirine plus Unboosted Protease Inhibitor
ETR may induce the metabolism and significantly reduce the drug exposure of unboosted PIs. Appropriate doses of the PIs have not been established (AII).22

Etravirine plus Fosamprenavir/Ritonavir
ETR may alter the concentrations of these PIs. Appropriate doses of the PIs have not been established (AII).22

Etravirine plus Tipranavir/Ritonavir
Tipranavir/ritonavir (TPV/r) significantly reduces ETR concentrations (AII).22

Nevirapine Initiated in ARV-Naive Women with CD4 Counts >250 cells/mm3 or in ARV-Naive Men with CD4 Counts >400 cells/mm3
Initiating NVP below these CD4 count thresholds increases the risk of symptomatic, and sometimes life-threatening, hepatic events.24-26 Patients with CD4 counts above these thresholds due to ART can safely switch to NVP (BI).27

Unboosted Darunavir, Saquinavir, or Tipranavir
The virologic benefit of these PIs has been demonstrated only when they were used with concomitant RTV, or in the case of DRV, also with COBI (AII).

Stavudine plus Zidovudine
These NRTIs are antagonistic in vitro28 and in vivo29 (AII).

Tenofovir Alafenamide plus Tenofovir Disoproxil Fumarate
This combination may be prescribed inadvertently, especially during transition from one formulation to another. There is no data supporting any potential additive efficacy or toxicity if TAF and TDF are used in combination.



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  12. Barnas D, Koontz D, Bazmi H, Bixby C, Jemsek J, Mellors JW. Clonal resistance analyses of HIV type-1 after failure of therapy with didanosine, lamivudine and tenofovir. Antivir Ther. 2010;15(3):437-441. Available at
  13. Food and Drug Administration. Caution issued for HIV combination therapy with Zerit and Videx in pregnant women. HIV Clin. 2001;13(2):6. Available at
  14. Kearney BP, Sayre JR, Flaherty JF, Chen SS, Kaul S, Cheng AK. Drug-drug and drug-food interactions between tenofovir disoproxil fumarate and didanosine. J Clin Pharmacol. Dec 2005;45(12):1360-1367. Available at
  15. Murphy MD, O'Hearn M, Chou S. Fatal lactic acidosis and acute renal failure after addition of tenofovir to an antiretroviral regimen containing didanosine. Clin Infect Dis. Apr 15 2003;36(8):1082-1085. Available at
  16. Martinez E, Milinkovic A, de Lazzari E, et al. Pancreatic toxic effects associated with co-administration of didanosine and tenofovir in HIV-infected adults. Lancet. Jul 3-9 2004;364(9428):65-67. Available at
  17. Barrios A, Rendon A, Negredo E, et al. Paradoxical CD4+ T-cell decline in HIV-infected patients with complete virus suppression taking tenofovir and didanosine. AIDS. Mar 24 2005;19(6):569-575. Available at
  18. Leon A, Martinez E, Mallolas J, et al. Early virological failure in treatment-naive HIV-infected adults receiving didanosine and tenofovir plus efavirenz or nevirapine. AIDS. Jan 28 2005;19(2):213-215. Available at
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  20. Podzamczer D, Ferrer E, Gatell JM, et al. Early virological failure with a combination of tenofovir, didanosine and efavirenz. Antivir Ther. 2005;10(1):171-177. Available at
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  22. Tibotec Inc. Intelence package insert. 2009. Available at
  23. Bethell R, Adams J, DeMuys J, et al. Pharmacological evaluation of a dual deoxycytidine analogue combination: 3TC and SPD754. Presented at Conference on Retroviruses and Opportunistic Infections; 2004; San Francisco, California.
  24. Baylor MS, Johann-Liang R. Hepatotoxicity associated with nevirapine use. J Acquir Immune Defic Syndr. Apr 15 2004;35(5):538-539. Available at
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